PROJECT SUMMARY Alveologenesis is the last step of lung maturation and generates ~95% of the gas- exchange surface area through formation of new septa. Disruption of alveologenesis, such as in bronchopulmonary dysplasia (BPD), leads to simplified alveoli, poor gas exchange and other respiratory deficiencies later in life. Myofibroblasts represents a key cell type in alveologenesis. In conventional two-dimensional analysis, myofibroblasts are depicted as dots at the tip of the finger-like septal crest, and are postulated to drive new septa formation by migrating into the lumen. We have found from three-dimensional analysis, that myofibroblasts are interconnected into rings, and rings are interconnected into nets. We postulate that it is the tensile property of this network of myofibroblasts that drive new septa formation. In mouse models of human lung development and disease, we will use genetic tools to investigate the role of myofibroblasts in normal alveologenesis, in alveolar simplification in BPD, and in regeneration of new septa after premature birth and BPD.